Apixaban, a factor Xa inhibitor, marketed as ELIQUIS® reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of deep vein thrombosis (DVT), is chemically described as 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide i.e. compound of formula (1).

U.S. Pat. No. 6,413,980 by Bristol-Mayer first disclosed Apixaban, but is silent on process to prepare Apixaban. It is disclosed in U.S. Pat. No. 6,967,208. It teaches use of multiple bases, TEA as acid scavenger and potassium tert-butoxide as strong condensing agent to produce iodo-lactam compound of formula (4) in 81% yield which is dichlorinated with phosphoruspentachloride (PCl5) in presence of chloroform to obtain morpholine compound of formula (5) in 63% yield and finally to iodo compound of formula (7) in 18% yield. Compound of formula (7) undergoes Ullmann reaction with piperidine-2-one catalyzed by copper or bivalent copper ions in presence of base at 130° C. for 24 hrs to obtain ester of compound of formula (8) followed by aminolysis in presence of ethylene glycol at 125° C. to Apixaban compound of formula (1) in 68% yield as depicted in Scheme 1.

PCT application 2012/168364 described process to prepare Apixaban by reacting Para-Iodoketolactam compound of formula (19) with trimethyl silyl chloride to obtain diene compound of formula (20). On cycloaddition with hydrazono compound of formula (6), it produces iodo compound of formula (7) in 63% yield. It, on Ullmann reaction with Pipyridin-2-one in presence of Copper produces ester compound of formula (8) in 67% yield followed by aminolysis with aq. Ammonia to obtain Apixaban compound of formula (1) as shown in scheme 2.

US '980 and WO '364 teach use of costly Iodo-compounds. Ullmann reaction/condensation involves use of copper besides drawbacks of harsh reaction conditions, high reaction temperature, long reaction time, high metal loading and the reaction has a reputation for erratic yields.
PCT application no. 2007/001385 discloses process to prepare of Apixaban by reacting 4-nitroaniline compound of formula (9) with compound of formula (3) in presence of K2CO3/KOH in the mixture of THF and chlorobenzene to obtain nitrolactam compound of formula (10). It, on dichlorination with PCl5 produces dichloro compound of formula (11). On dehydrohalogenation in presence of lithium carbonate, it produced mono chloro intermediate compound of formula (12). It, on reaction with hydrazono compound of formula (6) produced compound of formula (13). It is reduced to compound of formula (14) in presence of Pd/C in THF. It's reaction with, compound of formula (3) produces compound of formula (15). On cyclization and aminolysis with ammonia in presence of propylene glycol it produces Apixaban compound of formula (1) as depicted in Scheme 3.

WO '385 discloses use of expensive compound of formula (3), uses mixture of chlorobenzene and THF during chlorination of compound of formula (10) with PCl5. Work up procedure for isolation of compound of formula (11) is tedious and required expensive and hygroscopic strong base such as potassium ethoxide for the cyclization of compound of formula (15).
Synthetic communication, 2013, 43, 72-79 disclosed preparation of Apixaban using key intermediate compound of formula (18). The starting material 4-nitroaniline compound of formula (9) is reacted with compound of formula (3) in presence of triethyl amine/THF and cyclization is carried out in presence of potassium tert-butoxide to obtain compound of formula (10) which on chlorination with PCl5, followed by the condensation-elimination process with excessive morpholine produced nitro-morpholine compound of formula (16) in 78% yield followed by reduction of nitro group in presence of sodium sulfide to obtain aniline-morpholine compound of formula (17). Similarly second acylation/cyclization of compound of formula (17) with compound of formula (3′) in two steps, produced key intermediate having lactam compound of formula (18), wherein acylation is carried out in presence of triethyl amine/THF and cyclization is carried out in presence of potassium tert-butoxide. The compound of formula (18) is reacted with hydrazono compound of formula (6) to obtain ester compound of formula (8) which by aminolysis in methanolic ammonia solution produced Apixaban compound of formula (1) as depicted in Scheme 4.

Above non-patent literature discloses the use of TEA as an acid scavenger in the acylation reaction and then potassium tert-butoxide as a strong condensing agent in the subsequent cyclization during the preparation of compound of formula (10) and (18). It uses large volume of THF for preparation of (10) and (18) and Potassium tert-butoxide is hygroscopic, corrosive in nature. The chlorination of compound of formula (10) requires overall 25 volumes of chloroform with PCl5. which is undesirable. It uses Na2S, a potential environmentally hazardous compound for the reduction of nitro group. The reaction uses TEA and Potassium tert-butoxide in one pot acylation/cyclization sequence to prepare compound of formula (10) and (18). The overall process is costly.
CN 103626689 patent application discloses the reaction of aniline with compound of formula (3′) in presence of organic base in organic solvent to obtain compound of formula (24), which is then reacted with inorganic base to obtain compound of formula (21). Nitrating compound of formula (21) by conc. sulfuric acid and nitric acid produces compound of formula (10). The process to prepare (21) needs with two bases, organic base for acylation and inorganic base for cyclization. This multiplied material requirement has disadvantages associated with it. Reported yields in some stages are poor and it is silent on purity aspects.
U.S. Pat. No. 7,396,932 discloses complicated process to prepare the Apixaban N-1 crystalline form and H2-2 crystalline form.
US '980 disclosed the aminolysis of compound of formula (8) in presence of ammonia in ethylene glycol. Whereas WO '364 and Syn. Comm. 2013 disclosed aminolysis in aqueous ammonia in MeOH which produces acid impurity (8a). The acid impurity (8a) directly effect on yield of the final product and also involves extra purification process.
Above prior arts disclosed the use of expensive nitro aniline compound for the preparation of compound of formula (10).
Various processes are disclosed in CN101967145, CN102675314 and WO2013119328 for the preparation of Apixaban which are quite complicated.
In view of prior art methods available for the preparation Apixaban and its intermediates, there is a need for simple and cost effective processes as well as industrial and environmental friendly improved process for preparing Apixaban. Industry needs a simpler process that uses relatively inexpensive starting materials to provide significant economic advantages yet produces Apixaban in high yield.